Malaria is a protozoan infection whose pathogen is a malaria parasite. Infection with malaria has been found in not less than 100 countries in the world. According to estimation by the World Health Organization (WHO), about 500 million people are infected with malaria per year, and about 1.5 million people die of malaria every year. For treatment of malaria, drugs such as artemisinin, chloroquine, and atovaquone have been used. However, the number of types of the drugs is small compared to drugs for other infections. Moreover, in view of the current situation where malaria parasites resistant to the drugs described above are found, it is clear that development of novel therapeutic and prophylactic agents for malaria is an urgent task.
Invasion of malaria parasites into the body is mediated by anopheline mosquitoes. After infection of erythrocytes with the malaria parasites, the malaria parasites grow by degradation and utilization of proteins and lipids in the erythrocytes. When the nutrient becomes insufficient, the malaria parasites destroy the cell membrane, and cause infection of other erythrocytes. Therefore, natural compounds and synthetic compounds that are capable of specifically inhibiting this life cycle may be hopeful as novel antimalarial drugs. Artemisinin is activated by iron ion, and inhibits the function of an endoplasmic reticulum-type calcium pump, PfATP6, to exhibit the antimalarial activity. Chloroquine exhibits its antimalarial activity by inhibition of the detoxification process in which ferriprotoporphyrin IX is polymerized to produce hemozoin. Atovaquone specifically inhibits the electron transfer system driven by cytochrome bc1, to exhibit the antimalarial activity.
In recent years, “metallomics”, which is research for elucidation of roles and significances of trace metal elements (zinc, iron, copper, and the like) that are involved in life phenomena and cellular functions, is attracting attention. In particular, it has been suggested not only that zinc ion is deeply involved in maintenance of the structures of proteins, activation of metalloenzymes, nucleic acid synthesis, transcription regulation, second messengers, and the like, but also that it influences cell death, oxidative stress, carcinogenesis, and the like. In terms of association with malaria, it has been reported that, in the growth cycle of malaria parasites, the zinc ion concentration in the erythrocytes infected with malaria parasites increases in accordance with an increase in the DNA concentration (Non-patent Document 1). It has also been reported that N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), which is a zinc chelator, inhibits infection with malaria parasites (Non-patent Document 1).
As metal chelators having antimalarial activity, dipicolinic acid (DPA, Non-patent Document 2) and desferrioxamine (DFO; Non-patent Document 3) have been reported. However, neither of these exhibits high antimalarial activity (DPA, antimalarial activity ED50=1 mM; DFO, antimalarial activity IC50=21 μM, cell growth inhibition IC50=7 to 21 μM).